The mucosae and exocrine glands harbour the largest activated B-cell system of the body, amounting to some 80-90% of all immunoglobulin (Ig)-producing cells. The major product of these immunocytes is polymeric (p)IgA (mainly dimers) with associated J chain. Both pIgA and pentameric IgM contain a binding site for the polymeric Ig receptor (pIgR), or secretory component (SC), which is a requirement for their active external transport through secretory epithelia. The pIgR/SC binding site depends on covalent incorporation of the J chain into the quaternary structure of the polymers when they are produced by the local immunocytes. This important differentiation characteristic appears to be sufficient functional justification for the J chain to be expressed also by most B cells terminating at secretory effector sites with IgD or IgG production; they probably represent a "spin-off" from sequential downstream CH switching on its way to pIgA expression, thus apparently reflecting a maturational stage of effector B-cell clones compatible with homing to these sites. Observations in IgA-deficient individuals suggest that the magnitude of this homing is fairly well maintained even when the differentiation pathway to IgA is blocked. Certain microenvironmental elements such as specific cytokines and dendritic cells appear to be required for induction of IgA synthesis, but it remains virtually unknown why this isotype normally is such a dominating product of local immunocytes and why they have such a high level of J chain expression. Also, despite the recent identification of some important requirements in terms of adhesion molecules (e.g. integrin alpha 4 beta 7 and MAdCAM-1) that explain the "gut-seeking" properties of enterically induced B cells, the origin of regionalized homing of B cells to secretory effector sites outside the gut remains elusive. Moreover, little is known about immune regulation underlying the striking disparity of both the class (IgD, IgM) and subclass (IgA1, IgA2, IgG1, IgG2) production patterns shown by local immunocytes in various regions of the body, although the topical microbiota and other environmental stimuli might be important. Rational design of local vaccines will depend on better knowledge of both inductive and migratory properties of human mucosal B cells.

Peripheral T lymphocytes each express surface T cell receptor (TCR) alpha and beta chains of a single specificity. These are produced after random somatic rearrangements in TCR alpha and beta germline genes. Published model systems using mice expressing TCR alpha and/or beta chain transgenes have shown that allelic exclusion occurs conventionally for TCR-beta. TCR alpha chain expression, however, appears to be less strictly regulated, as endogenous TCR alpha chains are often found in association with transgenic TCR beta chains in TCR alpha/beta transgenic mice. This finding, coupled with the unique structure of the TCR alpha locus, has led to the suggestion that unlike TCR beta and immunoglobulin heavy chain genes, TCR alpha genes may make multiple rearrangements on each chromosome. In the current study, we demonstrate that the majority of TCR-, noncycling thymocytes spontaneously acquire surface expression of CD3/TCR. Further, we show that cultured immature thymocytes originally expressing specific TCR alpha and beta chains may lose surface expression of the original TCR alpha, but not beta chains. These data provide evidence that not only must multiple rearrangements occur, but that TCR alpha gene rearrangement continues even after surface expression of a TCR alpha/beta heterodimer, apparently until the recombination process is halted by positive selection, or the cell dies. Sequential rearrangement of TCR alpha chain genes facilitates enhanced production of useful thymocytes, by increasing the frequency of production of both in-frame rearrangements and positively selectable TCR alpha/beta heterodimers.

Integrin alpha v beta 3 is distinct in its capacity to recognize the sequence Arg-Gly-Asp (RGD) in many extra-cellular matrix (ECM) components. Here, we demonstrate that in addition to the recognition of ECM components, alpha v beta 3 can interact with the neural cell adhesion molecule L1-CAM; a member of the immunoglobulin superfamily (IgSF). M21 melanoma cells displayed significant Ca(++)-dependent adhesion and spreading on immunopurified rat L1 (NILE). This adhesion was found to be dependent on the expression of the alpha v-integrin subunit and could be significantly inhibited by an antibody to the alpha v beta 3 heterodimer. M21 cells also displayed some alpha v beta 3-dependent adhesion and spreading on immunopurified human L1. Ligation between this ligand and alpha v beta 3 was also observed to promote significant haptotactic cell migration. To map the site of alpha v beta 3 ligation we used recombinant L1 fragments comprising the entire extracellular domain of human L1. Significant alpha v beta 3-dependent adhesion and spreading was evident on a L1 fragment containing Ig-like domains 4, 5, and 6. Importantly, mutation of an RGD sequence present in the sixth Ig-like domain of L1 abrogated M21 cell adhesion. We conclude that alpha v beta 3-dependent recognition of human L1 is dependent on ligation of this RGD site. Despite high levels of L1 expression the M21 melanoma cells did not display significant adhesion via a homophilic L1-L1 interaction. These data suggest that M21 melanoma cells recognize and adhere to L1 through a mechanism that is primarily heterophilic and integrin dependent. Finally, we present evidence that melanoma cells can shed and deposit L1 in occluding ECM. In this regard, alpha v beta 3 may recognize L1 in a cell-cell or cell-substrate interaction.

The erbA<em>alpha</em> gene encodes two <em>alpha</em>-thyroid hormone receptor isoforms, TR<em>alpha</em>1 and TR<em>alpha</em>2, which arise from alternatively processed mRNAs, erbA<em>alpha</em>1 (<em>alpha</em>1) and erb <em>alpha</em>2 (<em>alpha</em>2). The splicing and alternative polyadenylation patterns of these mRNAs resemble that of mRNAs encoding different forms of <em>immunoglobulin</em> heavy chains, which are regulated at the level of alternative processing during B cell differentiation. This study examines the levels of erbA<em>alpha</em> mRNA in eight B cell lines representing four stages of differentiation in order to determine whether regulation of the alternatively processed <em>alpha</em>1 and <em>alpha</em>2 mRNAs parallels the processing of <em>immunoglobulin</em> heavy chain mRNAs. Results show that the pattern of <em>alpha</em>1 and <em>alpha</em>2 mRNA expression is clearly different from that observed for <em>immunoglobulin</em> heavy chain mRNAs. B cell lines display characteristic ratios of <em>alpha</em>1/<em>alpha</em>2 mRNA at distinct stages of differentiation. Furthermore, expression of an overlapping gene, Rev-ErbA<em>alpha</em> (RevErb), was found to correlate strongly with an increase in the ratio of <em>alpha</em>1/<em>alpha</em>2 mRNA. These results suggest that alternative processing of erbA<em>alpha</em> mRNAs is regulated by a mechanism which is distinct from that regulating <em>immunoglobulin</em> mRNA. The correlation between RevErb and erbA<em>alpha</em> mRNA is consistent with negative regulation of <em>alpha</em>2 via antisense interactions with the complementary RevErb mRNA.

Pregnancy-associated malaria is a major health problem, which mainly affects primigravidae living in malaria endemic areas. The syndrome is precipitated by accumulation of infected erythrocytes in placental tissue through an interaction between chondroitin sulphate A on syncytiotrophoblasts and a parasite-encoded protein on the surface of infected erythrocytes, believed to be VAR2CSA. VAR2CSA is a polymorphic protein of approximately 3,000 amino acids forming six Duffy-binding-like (DBL) domains. For vaccine development it is important to define the antigenic targets for protective antibodies and to characterize the consequences of sequence variation. In this study, we used a combination of in silico tools, peptide arrays, and structural modeling to show that sequence variation mainly occurs in regions under strong diversifying selection, predicted to form flexible loops. These regions are the main targets of naturally acquired immunoglobulin gamma and accessible for antibodies reacting with native VAR2CSA on infected erythrocytes. Interestingly, surface reactive anti-VAR2CSA antibodies also target a conserved DBL3X region predicted to form an alpha-helix. Finally, we could identify DBL3X sequence motifs that were more likely to occur in parasites isolated from primi- and multigravidae, respectively. These findings strengthen the vaccine candidacy of VAR2CSA and will be important for choosing epitopes and variants of DBL3X to be included in a vaccine protecting women against pregnancy-associated malaria.

Most mice which have recovered from influenza virus infection are immune to reinfection with the same influenza virus. This immunity could be abrogated by the intranasal instillation of anti-immunoglobulin A (anti-IgA) but not of anti-IgG or anti-IgM antiserum. Thus, IgA is the major, if not the sole, mediator of nasal immunity to influenza virus in immunocompetent mice.

ADPglucose pyrophosphorylase from developing endosperm tissue of starchy maize (Zea mays) was purified 88-fold to a specific activity of 34 micromoles alpha-glucose-1-P produced per minute per milligram protein. Rabbit antiserum to purified spinach leaf ADPglucose pyrophosphorylase was able to inhibit pyrophosphorolysis activity of the purified enzyme by up to 90%. The final preparation yielded four major protein staining bands following sodium dodecyl sulfate polyacrylamide gel electrophoresis. When analyzed by Western blot hybridization only the fastest migrating, 54 kilodaltons, protein staining band cross-reacted with affinity purified rabbit antispinach leaf ADPglucose pyrophosphorylase immunoglobulin. The molecular mass of the native enzyme was estimated to be 230 kilodaltons. Thus, maize endosperm ADPglucose pyrophosphorylase appears to be comprised of four subunits. This is in contrast to the respective subunit and native molecular masses of 96 and 400 kilodaltons reported for a preparation of maize endosperm ADPglucose pyrophosphorylase (Fuchs RL and JO Smith 1979 Biochim Biophys Acta 556: 40-48). Proteolytic degradation of maize endosperm ADPglucose pyrophosphorylase appears to occur during incubation of crude extracts at 30 degrees C or during the partial purification of the enzyme according to a previously reported procedure (DB Dickinson, J Preiss 1969 Arch Biochem Biophys 130: 119-128). The progressive appearance of a 53 kilodalton antigenic peptide suggested the loss of a 1 kilodalton proteolytic fragment from the 54 kilodalton subunit. The complete conservation of the 54 kilodalton subunit structure following extraction of the enzyme in the presence of phenylmethylsulfonyl fluoride and/or chymostain was observed. The allosteric and catalytic properties of the partially purified proteolytic degraded versus nondegraded enzyme were compared. The major effect of proteolysis was to enhance enzyme activity in the absence of added activator while greatly decreasing its sensitivity to the allosteric effectors 3-P-glycerate and inorganic phosphate.

Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the gene that encodes acid-beta-glucosidase (GlcCerase). Type 1 is characterized by hepatosplenomegaly, and types 2 and 3 by early or chronic onset of severe neurological symptoms. No clear correlation exists between the approximately 200 GlcCerase mutations and disease severity, although homozygosity for the common mutations N370S and L444P is associated with non- neuronopathic and neuronopathic disease, respectively. We report the X-ray structure of GlcCerase at 2.0 A resolution. The catalytic domain consists of a (beta/alpha)(8) TIM barrel, as expected for a member of the glucosidase hydrolase A clan. The distance between the catalytic residues E235 and E340 is consistent with a catalytic mechanism of retention. N370 is located on the longest alpha-helix (helix 7), which has several other mutations of residues that point into the TIM barrel. Helix 7 is at the interface between the TIM barrel and a separate immunoglobulin-like domain on which L444 is located, suggesting an important regulatory or structural role for this non-catalytic domain. The structure provides the possibility of engineering improved GlcCerase for enzyme-replacement therapy, and for designing structure-based drugs aimed at restoring the activity of defective GlcCerase.

The pathogenesis of immunoglobulin A (IgA) nephropathy (IgAN), the most prevalent form of glomerulonephritis worldwide, involves circulating macromolecular IgAA complexes in patients with IgAN. Soluble CD89 was identified as a glycoprotein with a 24-kD backbone that corresponds to the expected size of CD89 extracellular domains. To demonstrate their pathogenic role, we generated transgenic (Tg) mice expressing human CD89 on macrophage/monocytes, as no CD89 homologue is found in mice. These mice spontaneously developed massive mesangial IgA deposition, glomerular and interstitial macrophage infiltration, mesangial matrix expansion, hematuria, and mild proteinuria. The molecular mechanism was shown to involve soluble CD89 released after interaction with IgA. This release was independent of CD89 association with the FcRgamma chain. The disease was induced in recombination activating gene (RAG)2(-/-) mice by injection of serum from Tg mice, and in severe combined immunodeficiency (SCID)-Tg mice by injection of patients' IgA. Depletion of soluble CD89 from serum abolished this effect. These results reveal the key role of soluble CD89 in the pathogenesis of IgAN and provide an in vivo model that will be useful for developing new treatments.

BACKGROUND

Gender affects the incidence, prevalence, and progression of renal disease. In animal models of the disease, female sex appears to modify the course of progression. Hormonal manipulation by male or female castration also changes the course of renal disease progression, suggesting direct effects of sex hormones in influencing the course of these maladies.

OBJECTIVE

This review examines the pertinent animal and human studies assessing the role of gender, and strives to shed light on the possible physiologic mechanisms underlying the effect of gender, on renal disease progression.

METHODS

A summary and evaluation of past and recent studies describing the rate of renal disease progression in animal models and humans as it pertains to gender is provided. In addition, studies elucidating the factors involved in the more modest renal progression rate in females are reviewed and conclusions drawn. Relevant English-language publications were identified by searching the PubMed database from January 1990 until November 2007 using the search terms gender, sex, renal disease, and kidney.

RESULTS

In polycystic kidney disease, membranous nephropathy, immunoglobulin A nephropathy, and "chronic renal disease of unknown etiology," men progress at a faster rate to end-stage renal failure than do women. In type 1 diabetes mellitus, there is evidence that males are more likely to manifest signs of renal disease, such as proteinuria. The factors involved in this gender disparity may include diet, kidney and glomerular size, differences in glomerular hemodynamics, and the direct effects of sex hormones. In many, but not all, animal models of renal disease, estrogens slow progression rate. Several studies have recently evaluated the effect of selective estrogen receptor modulators on renal function in humans.

CONCLUSIONS

Further studies assessing the factors involved in the gender disparity in renal disease progression and the effects of hormonal treatments are warranted.

The amino acid sequence of the micro, chain of a human IgM immunoglobulin, including the location of all disulfide bridges and oligosaccharides, has been determined. The homology of the constant regions of immunoglobulin micro, gamma, alpha, and epsilon heavy chains reveals evolutionary relationships and suggests that two genes code for each heavy chain.

An enzyme-linked immunosorbent assay was adapted to measure immunoglobulin A (IgA), IgG, and IgM classes of human serum antibody to Campylobacter jejuni. Sera were tested from healthy controls, from ill persons at various intervals after exposure to an epidemiologically implicated vehicle for Campylobacter sp. enteritis, from persons exposed to these same vehicles who remained well, and from persons who chronically drank raw milk. The major antigens in the C. jejuni acid-washed antigen preparations from three different strains all migrated at about 30,000 and 63,000. Persons with Campylobacter enteritis developed rising serum IgA, IgG, and IgM antibodies during the second week after infection; IgG and IgM elevations persisted longer than did IgA. Exposed persons who remained well showed similar, but lower, antibody rises. Chronic raw milk drinkers had elevated IgG levels, but not IgM or IgA levels, whether or not they were acutely exposed to an implicated vehicle.

Dendritic cells (DCs) control the strength and quality of antigen-specific T and B cell responses. Recent advances point to a novel mechanism, in which metabolism of vitamin A into retinoic acid (RA) in DCs, regulate critical parameters of lymphocyte differentiation. First, RA enhances the induction of Foxp3(+) T regulatory cells by DCs. Thus, specific subsets of intestinal DCs and macrophages constitutively express RA synthesizing enzymes, and induce T regulatory cells. In addition, RA programs DCs to imprint mucosal homing properties on activated T and B cells, and enhanced induction of immunoglobulin-A (IgA) by B cells. Here, we review these recent advances, in the context of the pleiotropic effects of RA in regulating diverse biological processes.

Spleen cells from BALB/c mice immunized with heat-killed rough pneumococci (strain R36A) or spleen cells from normal mice immunized in vitro with the same antigen produce direct hemolytic plaques against sheep erythrocytes coated with pneumococcal C polysaccharide or conjugated with phosphorylcholine. Formation of plaques is specifically inhibited by phosphorylcholine or by antiserum to mouse immunoglobulin A myeloma protein which binds phosphorylcholine. Thus, the myeloma proteins and normal BALB/c antibodies share similar idiotypic determinants. This experimental system is suitable for probing the role of the antigen receptor in the immune response.

In this Opinion article, I address the role of the pre-B-cell receptor (pre-BCR) in the development of antigen-specific B cells in terms of immunoglobulin heavy chain (IgH) variable-region repertoire selection, precursor B-cell differentiation and proliferation, and IgH allelic exclusion. Comparisons with the role of the pre-T-cell receptor (pre-TCR) in T-cell development raise provocative questions. Why do B- and T-cell lineages both use a surrogate chain - the surrogate light chain and the pre-TCR alpha-chain, respectively - as a step to develop their repertoires of antigen-recognizing cells? What are the functions of the pre-BCR and pre-TCR in lymphocyte differentiation and antigen-receptor allelic exclusion? This article, together with the accompanying article by Harald von Boehmer, hopes to answer some of these questions.

Primary gastrointestinal lymphoma comprises a group of distinctive clinicopathological entities, most of which are not included in current lymph node-based lymphoma classifications. They may be of B- or T-cell type, with primary gastrointestinal Hodgkin's disease being extremely uncommon. Most low grade B-cell gastrointestinal lymphomas are of mucosa-associated lymphoid tissue (MALT) type, so called because they recapitulate the features of MALT rather than those of lymph nodes. Paradoxically, however, most MALT lymphomas arise in the stomach, which normally contains no organized lymphoid tissue. These gastric MALT lymphomas appear to arise in MALT acquired as a reaction to infection of the stomach by Helicobacter pylori and their growth can be influenced by eradication of this organism from the stomach. Low grade MALT lymphomas, which usually have a very favorable clinical course, may undergo high grade transformation; high grade tumours also may arise de novo and these probably also belong to the MALT group. Immunoproliferative small intestinal disease (IPSID) is a special form of MALT lymphoma with a restricted geographic distribution, which is characterized by synthesis of alpha heavy-chain immunoglobulin. Other gastrointestinal B-cell lymphomas include mantle cell lymphoma, which presents as lymphomatous polyposis, and Burkitt's or Burkitt-like lymphoma. Enteropathy (celiac disease)-associated T-cell lymphoma (EATL) is the most common primary gastrointestinal T-cell lymphoma. This is a clinically aggressive tumor that arises from the intraepithelial T-cell population, which is increased in celiac disease.

Animals contain an enormous load of non-pathogenic bacteria in the lower intestine, which exploit an environment with a stable temperature and abundant carbon sources. Our load of bacteria outnumbers our own cells. In order to survive with such a high number of organisms in very close proximity to host tissues the intestinal mucosa and its immune system is highly adapted. Mucosal immune responses are induced by small numbers of live commensal organisms penetrating the Peyer's patches and persisting in dendritic cells (DC). These DC can induce immunoglobulin A+ (IgA+) B cells, which recirculate through the lymph and bloodstream to populate the lamina propria and secrete protective IgA. Because DC loaded with commensal bacteria do not penetrate further than the mesenteric lymph nodes, immune induction to commensals is confined to the mucosa, allowing strong mucosal immune responses to be induced whilst the systemic immune system remains relatively ignorant of these organisms.

Secretory immunoglobulin A (SIgA) represents a first line of defense against mucosal pathogens by limiting their entrance. By using different strains of Salmonella typhimurium that target the two mechanisms of bacterial entry (microfold cell [M cell]- or dendritic cell-mediated), we demonstrated here that the distribution of bacteria after oral infection directed the type of induced immune response. M cell-penetrating invasive, but not noninvasive, S. typhimurium was found in large numbers in Peyer's patches (PPs), leading to the activation of immune cells and the release of fecal IgA. In contrast, both strains of bacteria were equally capable of reaching the mesenteric lymph node and the spleen and inducing IgG responses. These data suggest that PPs are absolutely required for the initiation of an IgA response to Salmonella, whereas they are dispensable for a systemic response. This compartmentalization could allow the fast generation of both mucosal and systemic acquired immunity to pathogens.

Degradation of acetylcholine receptors by cultured rat skeletal muscle cells was determined from the release of 125I from bound 125I-labeled alpha-bungarotoxin. Addition of immunoglobulin from patients with myasthenia gravis to the culture medium accelerated the degradation rate to a mean of 8.51 +/- 0.44 percent per hour, compared with the mean control rate of 3.97 +/- 0.14 percent per hour (P less than .001). A similar mechanism may possibly be involved in the autoimmune pathogenesis of myasthenia gravis in man.

Considerable evidence suggests that the high frequency of B cells committed to the IgA isotype in Peyer's patches is regulated by T lymphocytes. To understand more accurately the mechanism of this immunoregulation, an autoreactive T cell line from Peyer's patches was generated by culturing L3T4+ Peyer's patches T cells with syngeneic B cell blasts. The resulting T cell line, designated PT-1, and a clone derived from this line, PT-1.14, stimulated immunoglobulin secretion in spleen B cells with a preferential enhancement of IgA and IgG1 isotypes. Supernatant derived from concanavalin A-stimulated PT-1 or PT-1.14 cells could also enhance IgA secretion if spleen B cells were preactivated with lipopolysaccharide. Peyer's patches T cell supernatant did not contain IgA-specific binding factors. PT-1 supernatant scored positive in lymphokine assays for interleukin (IL)-2, IL-4 (B cell stimulatory factor 1), IL-5 (B cell growth factor II), and interferon-gamma, whereas PT-1.14 supernatant was positive for IL-4 and IL-5 and negative for IL-2 and interferon-gamma. Only IL-5 enhanced IgA secretion in lipopolysaccharide-activated B cells and this response was increased two- to three-fold by IL-4. These results suggest that the type 2 T helper subset which produces both IL-5 and IL-4 plays a primary role in regulating IgA expression.

We describe a mouse strain in which B cell development relies either on the expression of membrane-bound immunoglobulin (Ig) gamma1 or mu heavy chains. Progenitor cells expressing gamma1 chains from the beginning generate a peripheral B cell compartment of normal size with all subsets, but a partial block is seen at the pro- to pre-B cell transition. Accordingly, gamma1-driven B cell development is disfavored in competition with developing B cells expressing a wild-type (WT) IgH locus. However, the mutant B cells display a long half-life and accumulate in the mature B cell compartment, and even though partial truncation of the Ig alpha cytoplasmic tail compromises their development, it does not affect their maintenance, as it does in WT cells. IgG1-expressing B cells showed an enhanced Ca(2+) response upon B cell receptor cross-linking, which was not due to a lack of inhibition by CD22. The enhanced Ca(2+) response was also observed in mature B cells that had been switched from IgM to IgG1 expression in vivo. Collectively, these results suggest that the gamma1 chain can exert a unique signaling function that can partially replace that of the Ig alpha/beta heterodimer in B cell maintenance and may contribute to memory B cell physiology.

Four cDNA clones, pDR-alpha-1, pDR-alpha-2, pDR-alpha-3 and pDR-alpha-4, corresponding to the alpha chain of HLA-DR antigens, have been sequenced. Restriction maps and sequences suggest that all clones are identical apart from a single-base substitution present in pDR-alpha-1. Amino acid sequence data, together with the nucleotide sequence data, allowed the complete amino acid sequence to be predicted. The alpha chain is composed of 229 amino acids, of which 191 are exposed on the outside of the plasma membrane. The membrane-embedded portion of the chain consists of 23 hydrophobic amino acids. The succeeding 15 amino acids form the cytoplasmically localized hydrophilic tail. The extracellular portion, with carbohydrate moieties linked to Asn78 and Asn118, seems to be organized into two domains. The second domain, which contains the only disulfide bond of the alpha chain, displays amino acid sequence homology to immunoglobulin constant regions, to the second domain of the beta chain of a class II antigen, to the third domain of heavy chains of class I antigens and to beta 2-microglobulin. Thus the subunits of immunoglobulins, class I antigens and class II antigens are related evolutionarily.

OBJECTIVE

Enteric microorganisms are implicated in the pathogenesis of Crohn's disease (CD), but no clear bacterial or viral species has been identified. In this study, representational difference analysis (RDA) was used to isolate DNA segments preferentially abundant in lamina propria mononuclear cells of lesional mucosa vs. adjacent uninvolved mucosa.

METHODS

Two RDA-derived microbial sequences were isolated (I1 and I2) and identified as novel homologues of the ptxR and tetR bacterial transcription-factor families.

RESULTS

Quantitative competitive polymerase chain reaction of paraffin-embedded intestinal specimens from 212 patients showed that I2 DNA was present in many CD colonic lesions (43%), but was infrequent in other colonic specimens (9% of ulcerative colitis lesions and 5% of non-inflammatory bowel disease diseases; P<0.0001). I2 was prevalent in ileal specimens, regardless of disease status (43%-54%). Enzyme-linked immunosorbent assay analysis of 150 individuals with an I2 glutathione-S-transferase fusion protein showed frequent immunoglobulin A seroreactivity in CD (54% of patients), but infrequent seroreactivity in patients with ulcerative colitis, other inflammatory enteric diseases, or normals (10%, 19%, and 4%, respectively; P<0.001 to 0.00001).

CONCLUSIONS

These findings relate CD to a novel lesion-localized and immunologically associated bacterial sequence, suggesting that the microorganism expressing the I2 gene product may be related to CD pathogenesis.

OBJECTIVE

We have previously shown that E-selectin is expressed on endothelium in rheumatoid arthritis (RA) synovial tissues, and hence may be important in recruitment of leukocytes into the inflamed joint. In the present study, we determined whether other cellular adhesion molecules, including selectins and members of the integrin and immunoglobulin supergene families, are expressed in frozen synovium.

METHODS

We employed immunohistochemical staining to determine the distribution of CD31 (PECAM), CD44 (hyaluronate receptor), CD62 (P-selectin), Leu-8 (L-selectin), and the integrin subunits alpha 5 (VLA-5), alpha 6 (VLA-6), beta 1 (VLA 1-6), and beta 3 (vitro-nectin receptor), in synovial tissue from 9 RA and 9 osteoarthritis (OA) patients, and from 3 normal (NL) subjects.

RESULTS

P-selectin was expressed on vascular endothelium in all synovial tissues examined. L-selectin and alpha 5-integrin, while expressed on a variety of cell types, were not differentially expressed on RA synovial tissues. Integrin subunits alpha 6 and beta 1 were down-regulated on some RA synovial tissue components. In contrast, CD31 was expressed to a greater extent on RA than on OA lining cells and macrophages (P < 0.05). CD44 was expressed to a greater extent on RA or OA macrophages, lining cells, and fibroblasts compared with NL (P < 0.05). Integrin subunit beta 3 was strongly expressed on RA synovial blood vessels compared with NL (P < 0.05).

CONCLUSIONS

The expression of integrins VLA 1-6, and selectins P and L is not up-regulated in RA synovial tissues. CD31 and CD44 are up-regulated on RA macrophages and lining cells, CD44 on RA fibroblasts, and beta 3-integrin on RA blood vessels. The up-regulation of CD31, CD44, and beta 3-integrin in RA synovial tissues may help tip the balance of adhesive interactions toward passage and retention of leukocytes in the inflamed joint.